P809: BASELINE CHARACTERISTICS IDENTIFYING PATIENTS WITH MULTIPLE MYELOMA TREATED WITH IDECABTAGENE VICELEUCEL (IDE-CEL; BB2121) WHO ARE AT RISK FOR SEVERE/REFRACTORY INFLAMMATORY ADVERSE EVENTS
Authors: Afshin Mashadi-Hossein, Julie Rytlewski, MD Shamsuzzaman, Debashree Basudhar, Mandeep Takhar, Ana Kostic, Timothy B. Campbell, Salomon Manier, Yi Lin, Nathan Martin
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Inflammatory adverse events (iAEs) such as cytokine release syndrome (CRS) and neurotoxicity (NT) are common in patients with multiple myeloma (MM) treated with CAR T cell therapies such as ide-cel; CRS and NT observed with ide-cel are generally low grade and manageable with tocilizumab and corticosteroids. Identifying iAE risk with sensitivity and specificity is challenging, suggesting multifactorial etiology and limitations evaluating dynamic processes at specific timepoints. Macrophage activation syndrome (MAS; per Common Terminology Criteria for Adverse Events) has a specific molecular profile representing a homogeneous subgroup within CRS, tending to be more severe/refractory to front-line management. Aims: Using longitudinal data on post-infusion soluble factors, we aimed to develop a candidate post-infusion inflammatory risk score based on MAS molecular signature and determine associations with baseline characteristics in patients with MM. Methods: Statistical learning tools were applied to the longitudinal profile of 34 factors measured over 28 days after ide-cel infusion in 291 patients from KarMMa (NCT03361748) and KarMMa-2 (NCT03601078) to extract features describing the profiles. Unsupervised machine learning-based clustering was applied to these features and enrichment for MAS cases within each cluster was assessed. A metric describing membership in a cluster of interest was used as a candidate post-infusion inflammatory risk score for further correlative analyses. Results: Patients with MAS had cytokine profiles consistent with high levels of pro-inflammatory signaling across multiple inflammatory cell types. Cytokine profiles of MAS were qualitatively similar to those of CRS/NT; however, unsupervised clustering showed a distinct group of patients with MAS. A metric of similarity to the MAS-enriched cluster was defined as a candidate post-infusion inflammatory risk score, posited to identify patients more likely to have more severe/refractory iAEs. This inflammatory risk score positively correlated with CRS and NT grades and frequency of tocilizumab usage (Kruskal–Wallis test; all P < 0.001). A prototype predictive model based on baseline patient and clinical characteristics strongly correlated with post-infusion inflammatory risk score (Pearson; ρ= 0.88). Low blood counts, higher tumor burden, and elevated levels of inflammatory markers on the day of ide-cel infusion were associated with a higher inflammatory risk score. Summary/Conclusion: A molecular profile of severe/refractory iAEs was preliminarily identified in ide-cel-treated patients with MM. This profile enabled derivation of a candidate post-infusion inflammatory risk score and a prototype predictive model of this risk score based on patient baseline characteristics was developed. These results may help identify patients at risk for severe/refractory iAEs, who may be potential candidates for closer monitoring or novel interventions, and warrant further study. Keywords: Cytokine release syndrome, Risk factor, CAR-T, Multiple myeloma